A Phase II Study to Assess the Efficacy and Safety of Luveris® (Lutropin Alfa) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age

Condition(s) targeted: Infertility; Ovulation Induction

Intervention: Lutropin alfa for injection (r-hLH) + r-hFSH (Drug); r-hFSH preparation (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Merck KGaA

Official(s) and/or principal investigator(s):
Dr.Enrique Granados, Study Chair, Affiliation: Merck Serono Spain, an affiliate of MerckKGaA, Darmstadt, Germany

Ovarian reserve is related to chronological age and age 35 years is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. New therapeutic schemes are sought to improve follicular response in ovarian ageing because of the increasing number of infertile women aged > 35 years who are seeking pregnancy. The advent of gonadotropin releasing hormone analogue antagonist (GnRHant) offers new perspectives to address the advanced reproductive age since it allows for preventing premature luteinizing hormone (LH) surges while not causing suppression in the early follicular phase. Gonadotropin releasing hormone analogue antagonist are administered in the latter stage of the ovarian stimulation to prevent LH surge by competitive blockade of GnRH receptors, thus producing a marked decrease in LH levels just when the interplay between follicle stimulating hormone (FSH) and LH is important to complete follicular development and oocyte competence. Some studies in the past have shown the potential of recombinant human LH (r-hLH) supplementation in older reproductive age to improve oocyte quality, but these studies are of small size and did not provide data on the physiological mechanism behind the benefit obtained.

This randomised, comparative with parallel control, phase II study will be conducted in infertile female subjects aged 35-42 years undergoing in-vitro fertilisation/intra cytoplasmic sperm injection (IVF/ICSI), to investigate whether the addition of r-hLH (when the lead follicle is > 14 mm in size), to the standard protocol with recombinant human FSH (r-hFSH) under GnRHant, improves the number and quality of oocytes retrieved, implantation rate, and pregnancy rate, while assessing the hormonal milieu in ovarian follicular fluid. Comparison will be performed against ovarian stimulation without addition of r-hLH, i. e. with r-hFSH under GnRHant alone.

Official title: Lutropin Alfa (Luveris®) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age: a Phase II Trial

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Efficacy

Safety

Secondary outcome: Secondary efficacy variables

Detailed description: Preclinical pharmacology studies have demonstrated that r-hLH has a LH/human menopausal gonadotropin (hCG) receptor affinity similar to pituitary hLH (p-hLH), and is biologically active in-vitro in stimulating steroidogenesis and in promoting oocyte germinal vesicle breakdown. Several clinical studies in the past have investigated the usefulness of r-hLH supplementation in normal ovulatory women undergoing ART and almost all of them have been identified as sub-populations of subjects who will benefit, when r-hLH is added along with FSH.

OBJECTIVES

Primary objectives:

- To assess the efficacy of mid-follicular addition of r-hLH versus no addition of r-hLH,

in subjects aged between 35 and 42 undergoing COS with r-hFSH under GnRH antagonist protocol prior to IVF or ICSI, in terms of oocyte number and quality

- To assess the safety of using r-hLH in combination with r-hFSH under a GnRH antagonist

protocol, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerance

Secondary objectives:

- To complete efficacy with additional assessments such as follicular development, oocyte

fertilisation, embryo quality and pregnancy rates

- To investigate the underlying mechanism of potential improvement in oocyte quality by

measuring hormonal [LH, FSH, T, estradiol (E2), and human chorionic gonadotropin (hCG)] levels in follicular fluid

All subjects will undergo treatment with r-hFSH at a daily dose of 300-450 IU by subcutaneous (s. c.) route starting on the stimulation Day 1 until r-hCG administration. Upon detection of a lead follicle > 14 mm in size, GnRHant 0. 25 mg/day s. c. administration will be initiated and continued up to r-hCG administration day. Subjects will then be randomly allocated (at any time between stimulation Day 1 (S1) and GnRHant initiation day) either to additional treatment with r-hLH at a daily fixed dose of 150 IU or continue treatment with r-hFSH alone. Gonadotropin releasing hormone antagonist and combined treatment with r-hLH + r hFSH or r-hFSH alone will be administered until at least one follicle > 18 mm and two additional follicles > 16 mm are present and E2 levels are commensurate with the number and size of follicles present. A single injection of 250-500 mcg of r-hCG, will be given to induce final follicular maturation within 36 hours of the last r-hLH and/or r-hFSH injections and on the same day of the last GnRHant morning administration. Oocytes will be retrieved 34-38 hours after r-hCG administration, assessed, and fertilised in-vitro by ICSI. Not more than 3 embryos will be replaced on day 2 or 3 after ovum pick-up (OPU). The luteal phase will be supported by a daily vaginal administration of natural progesterone, starting after OPU and continuing either up to menstruation or the pregnancy test or, if the subject is pregnant, for at least 30 days after laboratory evidence of pregnancy. Each subject will be followed-up and the treatment outcome (pregnancy or menstruation) will be recorded.

For all subjects who received r-hCG and do not menstruate, a blood sample will be collected for local determination of serum ß-hCG level between post-hCG days 15-20. If positive (ß-hCG > 10UI/l), it should be confirmed by performing a second test within one week later. An ultrasound scan (US) will be performed at post-hCG days 35-42 on all subjects who will become pregnant provided that no miscarriage has occurred. The number of foetal sacs and foetal heart activity will be recorded. Active follow-up of all pregnancies will be performed, including those subjects withdrawn from the study.

Minimum age: 35 Years. Maximum age: 42 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Pre-menopausal female subjects, aged between 35 and 42 years willing to conceive

- Subjects with baseline (early follicular, day 2-5) FSH serum level ≤ 10 IU/l as well

as LH and E2 levels within local normal range

- Subjects having regular spontaneous menstrual cycle lasting 25-35 days

- Subjects with infertility justifying IVF/ICSI-embryo transfer treatment

- Subjects programmed for COS with r-hFSH under GnRH antagonist protocol

- Sperm from current partner suitable for IVF/ICSI according to local lab, unless sperm

donor is foreseen

- Subjects with both ovaries

- Subjects with uterine cavity able to sustain embryo implantation or pregnancy

- Subjects with normal papanicolaou smear within 6 months prior to study entry

- Subjects with body mass index (BMI) < 30 at stimulation start

- Confirmation that the subject is not pregnant by a negative β-hCG test (urine or

blood) prior to starting r-hFSH administration

- Subjects willing and able to comply with the protocol for the duration of the study

- Subjects who have given informed consent prior to any study-related procedure not

part of normal medical care

Exclusion Criteria:

- Subjects or her partner known to be human immunodeficiency virus or Hepatitis-B

virus/Hepatitis-C virus positive

- Subjects with any clinically significant systemic disease; tumours of the

hypothalamus and pituitary gland; ovarian, uterine or mammary cancer; hormonal abnormality and/or medical, biochemical, hematological condition which in the judgement of the investigator may interfere with gonadotropin treatment

- Subjects with more than 2 previous ART cycles

- Subjects who have cancelled two previous cycles

- Cryopreserved embryos from previous ART cycles

- Subjects with unexplained gynaecological bleeding

- Subjects with polycystic ovaries, ovarian enlargement or cyst of unknown aetiology

- Any contraindication to being pregnant and/or carrying pregnancy to term

- Subjects with known allergy to gonadotropin preparations or any of the excipients

- Subjects with any active substance abuse or history of drug, medication or alcohol

abuse in the past 5 years

- Subjects who have previously entered into this study or simultaneous participating in

another clinical drug trial

- Subjects who have refused or inability to comply with protocol

Instituto Marqués, Barcelona 08034, Spain; Recruiting
Dr. Marisa López-Teijón, Phone: + 34 93 285 82 16
Dr. Marisa López-Teijón, Principal Investigator

Starting date: January 2008
Last updated: September 2, 2010